Substituted 4,4&#39;-diaminodiphenyl sulfones and process of making same



Patente an. 1, 1947 'suns'rrru'rnn ar-nmmnorirrnsnrr.

SULFONES AND rnocnss or MAK- ING SAME Lucas P. Kyrides, St. Louis, Mo., asslgnor to Monsanto Chemical Company, St. Louis, Mo., ,a corporation oi Delaware No Drawing. Original application March 20.

1943, set-n1 No. 479,915. Divided and this application October 3, 1945, Serial No. 620,159

This invention relates to certain new deriva- 8 Claims. (Cl. 260-397-6) tives of 4,4'-diaminodiphenyl sulfone and to the process-oi. producing them. 1

This application is a division of my co-pendin application, Serial Number 479,915, filed March These new products have been found to' possess therapeutic activity in the treatment oi various diseases.

These new derivatives may be represented by the following general formula:

in which X and Y represent difierent radicals selected from the group consisting of ,sulfide, disulfide, thionyl, sulfone and oxygen radicals.

In preparing these new products, the procedure in general is the following:

To a solution (or suspension) of one molecular equivalent of 4,4-diaminodiphenyl sulfone in a suitable solvent, such as acetone, methyl alcohol, ethyl-alcohol, ethylene glycol or dioxane, is added two molecular equivalents of the anhydride halide or mono-ester acyl halide of an acid selected from the group consisting of diglycollc acid, thiodiglycolic acid, dithiodiglycolic "acid, thionyl diglycolic and sulfondiacetic acids. The reaction mixtur is desirably refluxed for several hours and the solvent thereupon removed by evaporation under reduced pressure. The residue and oil are solidified by treatment with water. The solid material is filtered oil and dried. The product maybe purified by dissolution in alcohol, filtration through charcoal, addition of water and agitation until crystallization of the product is efiected. Prepared in this manner, the product may retain some water of crystallization,

which may be removed if desired by drying the product, for example, in a stream of heated air or in vacuo at a temperature below the decomposition point of the product.

Fonthe preparation of the monoacylamino derivative. one molecular equivalent of the anhydride, halide or mono-ester acyl halide is employed in place of two molecular equivalents. As an alternative to the diacylamino compounds, mixed acylamino compounds may be prepared by first reacting one molecular equivalent of one of the anhydrides in the group hereinbeiore described with the diaminodiphenyl sulfone and then reacting one molecular equivalent of another of the anhydrides in the group hereinbeiore described or any other suitable anhydride,

L for example, acetic anhydride. Also, the order 'ployed for therapeutic purposes.

of the substitution may be reversed, for example, first reacting acetic anhydride and then reacting one of the anhydrides in the group hereinbefore described.

The 4,4'-diaminodiphenyl suli'one is desirably obtainedvby refluxing a mixture of parachloronitrobenzene and sodium sulfide in water, reacting the resulting p-aminothiophenolate with a molecular equivalent of parachloronitrobenzene, acylating the resulting 4-nitro-4'-aminodiphenyl sulfide with acetic anhydride, oxidizing the sulfide to the sulfone, removing the acetyl residue by acid hydrolysis and reducing the 4-nitro-4'-aminodiphenyl sulione to the diamino compound.

A desirable procedure for obtaining the monoacylamino derivatives of the present invention comprises sulfide with a molecular equivalent of the anhydride of one oi. the acids selected from the group hereinbefore described, oxidizing the 4-nitro-4'-acylaminodiphenyl sulfide to the sulione and subsequently reducing the nitro residue to the amine.

A desirable procedure for obtaining the diacylamino derivative of the present invention comprises reducing 4-nitro-4'-aminodiphenyl sulfide to 4,4'-diaminodiphenyl sulfide, acylatlng the sulfide with two molecular equivalents of the anhydride of one of the acids selected from the group hereinbeiore described, and subsequently oxidizing the sulfide to the sulione.

Both the fre acids and the salts of the compounds of the present invention may be em- Examples of the alkali metal salts are the di-sodium, di-potassium, and mixed sodium and potassium salts of N-diglycolyl-N-thiodiglycolyl-4,4f diaminodiphenyl sulfone. These salts may be prepared, for

example, by dissolving a molecular equivalent of the derivative in an aqueous solution of sodium carbonate containing fromone to two molecular equivalents of the alkali-metal carbonate and recovering the salt, by evaporation of the water. Examples of the alkaline-earth metal salts are the calcium and magnesium salts. The arm monium salts and substituted ammonium salts may also be employed for therapeutic purposes, and also the mixed ammonium and alkali metal or alkaline-earth metal salts. In the therapeutic administration of the derivatives of this invenacylating 4-nitro-4f-aminodiphenyl with 2500 cc. of water.

auaaaa The following preparations and examples serve to illustrate the general process. It is to be understood, however, that these examples do not limit the invention since other methods for preparing the compounds of this invention are contemplated.

. Pnrrmrron No. 1

4-nitro-4'-aminodiphenyl sulfide This substance may be prepared according to the method described in J. Am. Chem. Soc., 61,

. 2763 (1939), in which p-chloronitrobenzene is re- Paarmrrox No. 2 4-nitro-4'-aminodiphenyl sulfone A solution of 187 grams of 4-nitro-4-aminodiphenyl sulfide, prepared according to the method described under Preparation No. 1, in 510 cc. of glacial acetic acid and 161 cc. of acetic anhydride was refluxed for two hours to effect acetylation of the amino group. 800 cc. of glacial acetic acid was then added and the temperature was adjusted to 90 C. During three hours, 317 cc. of 30% hydrogen peroxide was added dropwise. The temperature was maintained at 90 C. for an additional halfhour and the mixture was cooled and diluted The crude 4-nitro-4'- acetylaminodiphenyl sulfone was filtered off and washed with water. This product was mixed with 360 cc. of concentrated hydrochloric acid, 1080 cc. of water and 300 cc. of ethyl alcohol. After refluxing 'for about ten hours, the mixture was cooled to 30 C., and neutralized with 50% soda lye. The precipitated material was filtered off, washed with water and dried at 80 C. Upon analysis, the product was found to be 4-nitro-4-aminodiphenyl sulfone. I

Pxrzraaa'rrou No. 3

4,4-dz'aminodiphenyl sulfide s This substance may be prepared according to the method described in J. Am. Chem. 506., 61, 2763 (1939), in which a suspension of 4-nitro-4'- aminodiphenyl sulfide is treated simultaneously with tin turnings and hydrochloric acid to reduce the nitro group to amino. After the reduction,

' purified product the product was precipitated from'the reaction mixture with alkali, filtered therefrom, alcohol and recovered by precipitation with water and filtration. The product may be recrystallized from 50% alcohol; f v

Pwmrrox No. 4 4 4,4'-diaminodiphenvl sul jo n ei This substance was prepared according tothe method described in J. Am. ,Chem. Soc., 61, 2763 (1939) in which 4,4-diaminodiphenyl sulfide and acetic anhydride were refluxed and the resulting 4,4'-diacetylaminodiphenyl sulfide was recovered, oxidized to the sulfone with potassium dichromate in the presence of sulfuric acid and glacial acetic acid, recovered from the reaction mixture and the two acetyl radicals hydrolyzed oil! with the aid of hydrochloric acid. The 4,4'-diaminodiphenyl sulfone is thereupon precipitated by adding sodium carbonate and the precipitate is recovered and washed. The product may be purifled by refluxing with aqueous alcohol and the recovered by adding water. to the solution, cooling with ice and separating the solid product by filtration. In the acylation step any suitable anhydride, for example; succinic anhy- CHr-C /0 C Hr-C This substance may be prepared method described in Annalen, in which diglycolic chloride, excess acetyl chloride is distilled off and the residue is dissolved in warm chloroform and crystallized therefrom on cooling.

PREPARATION No. 6 Thiodiglycolic anhydride CHr-C s o 7 This substance may be prepared according to the method described in Annalen 273, 68 (1893),

according to the 259, 190 (1890),

. in which dry thiodiglycolic acid and acetyl chloride areheated, excess acetyl chloride is distilled ed and the residue is dissolved in warm chloroform and'crystallized therefrom on cooling.

PREPARATION No. '7 Dithiodiglucolyl dichloride o Cl-PJ-CHr-S-S-CIIg-(J-Ol Dlthiodiglycolic acid may be prepared according to the method described in German Patent No. 194,039, in which sodium chloracetate and sodium-disulfide are reacted and the product is acid is refluxed with acetyl recovered ,ifrom the reaction mixture. In the preparation of the acyl dichloride, 21.1 grams of dithiodiglycolic acid and 23 grams of thionyl chloride were refluxed in 50 cc. of benzene for three hours. The liquid reaction mixture was decanted from insoluble material and distilled until the solvent and excess thionyl chloride were removed. The residue, dithiodiglycolyl dichloride, may be purified byconventional methods.

As an alternative to the dichloride, the monoester acyl halide. for example, monomethyl dithiodiglycolyl chlorlde,'may.be prepared and used. The bromides and other halidesof dithiodiglycolic acid may be used. In using the halides and mono-ester halides in preparing the compounds of the present invention, it is necessary, after the amide has been formed, to hydrolyze off the remaining halide residue or mono-ester residue I r in order to obtain the free carboxyl compound.

, Paxrmrron No. 8 rhi gwldialucolic anhzldride Cilia-0 O GHQ-C;

Thionyldiglycolic acid may be prepared according to the method described in J. Chem. Soc. (London), 93, 1834, in which thiodigly'colic' acid is treated with an excess of hydrogen peroxide and the product is recovered from the reaction mixture. The anhydride may be prepared according to the methods described inPreparations prepared according to the methods in Preparations Nos. 5 and 6.

Exulru: I

- lll-diglycolyl-Lf-diaminodiphcnyl sulfone i I? @n-c-cm-o-cm-coon 0 o g O I A mixture of 24.6 grams of 4-amino-4'-nitrodiphenyl sulfide, 75 cc. of acetone and 12 grams of dlglycolic anhydride was refluxed for two hours and thereafter allowed to stand for ten hours at 25 C. The reaction product, N-diglycoly1-4- amino-4'-nitrodiphenyl sulfide, was crystallized from the mixture as a yellow solid and was filtered olf, washed with acetone and dried. The acetone A solution of 27.8 grams of this material in 80 cc. of glacial acetic acid was prepared and heated to 90 C. During three hours, 31.7 cc. of 30% hydrogen peroxide was added dropwise to the solution. The temperature was maintained at 90 C. for an additional half hour. Thereafter the mixture was cooled and diluted with 100 cc. of water. The precipitated product was filtered oif, washed with water and dried at 80 C. The product of this reaction was N-diglycclyl-4-nitro-4'-amino-' diphenyl sulfone.

As an alternative preparation of N-diglycolyl-4- nitro.-4'-aminodiphenyl sulfone, a mixture of 27.8 grams of 4-nitro-4'-aminodiphenyl sulfone, 75 cc. of acetone and 12.0 grams of diglyco'lic anhydride was refluxed for two hours and cooled to 25 C.

Upon standing, a 'yellow solid crystallized out. The product was filtered ofi, washed with acetone and dried; weight 32 grams. The acetone filtrate was evaporated, the residual oil was treated with 100 cc. of water and the mixture was stirred until the product solidified. The c ystals were filtered ofi, washed with water and dried at 80 C. The total yield was 39.4 grams (100% A mixture of 39.4 grams of N-diglycolyl-4-nitro-,4'-aminodlphenyl sulfone with 35.7 grams of granulated tin in 250 cc. of alcohol was treated with 250 cc. of 10% hydrochloric acid. The mixture was stirred for four hours at 40-45 C., filtered, and the tin was removed fromthe filtrate by treatment with hydrogen sulfide. Excess hy-- drogen sulfide was dissipated by means of a stream of air or by placing the solution under vacuum. The solution was alkalinized with sodium bicarbonate, evaporated to dryness under reduced pressure and the residue was recrystals lized. The product was N-diglycolyl-4,4-diaminodiphenyl sulfone.

The nitro compound also can be reduced catalytically with hydrogen, using a hydrogenation catalyst.

- Exmnn' II N-thiodiolyc0lyl-4 A-diamin0diphenyl sulfone A mixture of 27.8 grams of 4 -amino-4'-nitrodiphenyl sulfone, 75 cc. of acetone and 14 grams of thiodiglycolic anhydride was refluxed for two hours. At this time; 100 cc. of water was added and the acetone was evaporated from the mixture. The-solid material was filtered oil, washed with water and dried at 80 C. The product of this reaction was N-thiodiglycolyl-4-amino-4'- nitrodiphenyl sulfone. A mixture of 41.0 grams of this product with 35.7 grams of granulated tin in 250 cc. of alcohol was stirred with 250 cc. of

mother liquor was evaporated. Water was added to the residual oil and the mixture was strred until the oil was solidified. "'I'he'solid material was filtered, washed with water and dried at C. a

10% hydrochloric acid at 4045 C. for four hours. Solids were removed by filtration and the filtrate was freed from "tin by treatment with hydrogen sulfide. Excess hydrogen sulfide was dissipated by means of a stream of air or by placing the solution under vacuum. The solution was alkalinized with sodium bicarbonate, evaporated to dryness under reduced pressure and the residue was purified by recrystallization.

The nitro compound also may be reduced with hydrogen using a hydrogenation catalyst. and some suitable solvent, such as an -alcohol, dioxane, etc.

' thiodiglycolyl chloride in place of proportions.

Exunrm III N-dz'thiodialycolyl-4,4'-diaminodiprwn11l sulfon EXAMPLE IV N-thionyZdigylcolj/l-4A'-diaminodiphenyl suljone i i i Orr-o-om-t-cm-coon This product may be prepared according to the method of Example 11, using thionyldiglycolic anhydride in place of thiodiglycolic anhydride, with corresponding changes in Exams: V I N-su'ljondiacetyl-M'-diaminodiphenyl sulfone This compound may be prepared according to the method of Example'l, replacing dislycolic anhydride with sulfondiacetic anhydride.

It is further a feature of this invention that sulfondiacetic anhydride may be replaced with thiodiglycolic anhydride and the sulfide radicals of the thiodigiycolyl and aminodiphenyl sulfide residues oxidized simultaneously with an excess of hydrogen peroxide to the corresponding sulfones. For example, the diglycolic anhydride Example I may be replaced with 14 grams or thiodiglycolic anhydride and the quantity or 80% hydrogen peroxide increased to 63.4 cc. or twice that required for the oxidation or one sulfide residue to the corresponding sulfone residue.

EXAMPLE Y1 N-diglycolyl-N'-thiodiglycolul-4,4'-diaminodiphenyl sulfone o=s=o I O-N-C-CHr-S-CHrCOOH A mixture of 39.4 grams of N-diglycolyl-4,4'- diaminodiphenyl sulione, prepared according to the method of Example I, '75 cc. of acetone and 14 grams of thiodiglycolic anhydride was refluxed for two hours. 100 cc. of water was added and the acetone was evaporated. The residue was filtered off, washed with water and dried at 80 C. The product was N-diglycolyi-N'-thio.diglycom-4,4-diaminodiphenyl sulione.

Exsuruvll N-thiodiglucolyl-N'-sulfondiacetyl -4,4'diamtnothe stoichiometrical fone compounds embodying the acyl residues deamine salt with the aid of diphenyl suljone A mixture or 41 grams or diamincdiphenyl sulfone, prepared according to the method of Example 11, 75 cc. of acetone and 18 grams of sulfondiacetic anhydride was refluxed for two hours. 100 cc. of water was added and the acetone was evaporated. The solid material was filtered oil, washed with water and dried at C. The product was N-thiodiglycolyl-N'- sulfondiacetyl-4,4'-diaminodiphenyl sulione.

As an alternative procedure, N-sultondiacetyl- 4,4'-diaminodiphenyl sulrone may be prepared according to the method of Example I, using thiodiglycolic anhydride in place of diglycolic anhydride and oxidizing the thio residue to sulrone along with 'the diaminodiphenyl sulfide residue according to the alternative method described in Example V. This material may then be acylated with thiodiglycolic anhydride according to the method described in Example 11.

Other mixed N-acyl-4,4'-diaminodiphenyl sulrived from the anhydrides described herein may also be prepared by the method's described in the aforedescribed examples. Among these acyl derivatives are the following:

N-diglycolyl-N'-dithiodiglycolyl N-diglycolyl-N'-thionyldiglycolyl N-diglycolyl-W-sulfondiacetyl N-thiodiglycolyl-N'-dithiodiglycolyi N-dithiodiglycolyl-N'-suliondiacetyl lI-thionyldiglycolyl-N'-suliondiacetyl N-thionyldiglycolyl-N'-dithiodiglycolyl In place of the anhydrides described hereinbetore, the acyl halides or the mono-ester acyl halides or the acids may be employed. In this event, after condensation of the acyl dihalide or the mono-ester acyl halide with an amino group, the hydrolysis of the residual halide or mono-ester residue is made necessary in order to expose the free carboxyl radical of the acid residue.

As a further alternative, the diaminodiphenyl sulfone or 4-nitro-4-aminodiphenyl sulfone may be condensed with the acid directly, forming first an amine salt and subsequently dehydrating the heat and, if desired, a dehydration catalyst to accelerate the reaction. The dehydration reaction may be conducted at reduced pressure.

The derivatives of the present invention may be recovered as the hydrates: For example, N- thiodiglycolyl-N'-diglycolyl-4,4'-diaminodiphenyl sulione may berecovered as the dihydrate and N-thiodoglycolyl N sulfondiacetyl-4,4-diaminodiphenyl sulfone as the trihydrate. This water of hydration may be removed by heating the respective compounds in a stream of heated air or in vacuo below the temperature at which decomposition begins.

Iclaim: V

1. A substituted 4,4'-diaminodiphenyl sulrone N-thiodislycolyl-4.

which is represented by the following general formula:

in which X and Y represent different'divalent 10 radicals selected from the group consisting of oxide, sulfide, disulflde, thionyl and sulfone radicals.

2. The product set forth in claim 1 in which at least one carboxyl hydrogen is replaced by a. 15

metal ion selected from the group consisting of alkali-metal, alkaline-earth metal, ammonium and substituted ammonium ions.

3. N-diglycolyl-N'-thiodiglycolyl-4,4'-diaminodiphenyl sulfone.

4'. N-thiodiglycolyl N sultondiacetyl-4,4'-di- I amlnodiphenyl sulfone.

5. N-thiodiglycolyl-N'-dithiodiglycolyl-4,4'-di aminodiphenyl sulfone.

s. The disodium salt of N-diglycolyl-N-thiodi- LUCAS P. KYRIDES. 

